Two distinct polyomaviruses, called BKV and JCV, chronically infect the human urinary tract. Most healthy adults are stably infected with both viruses and occasionally shed infectious virions in the urine. Although BKV and JCV aren't known to cause overt symptoms in healthy individuals, each of the two viruses can cause severe pathology in immunocompromised individuals. Most notably, BKV causes acute kidney damage in up to 10% of kidney transplant recipients. In AIDS patients and patients taking certain immunosuppressive drugs, JCV can cause a fatal brain disease called progressive multifocal leukoencephalopathy (PML). A further concern is that a controversial body of evidence has linked both BKV and JCV to various forms of cancer, including prostate and colorectal cancer, respectively. Our goal for this project is to develop preventive vaccines that might protect at-risk patients against BKV associated nephropathy (BKVN) or PML. The vaccines would draw on the same approach that led to the current highly successful vaccines against human papillomaviruses - specifically, the BKV or JCV vaccine would be composed of recombinant virus-like particles (VLPs) composed solely of the viral major capsid protein VP1. The VLP vaccine would be aimed at eliciting antibody responses capable of neutralizing the infectivity of BKV or JCV virions. To be successful, viruses must avoid being recognized by neutralizing antibodies elicited by previous infections. This evolutionary pressure drives the development of distinct viral serotypes that are not cross-recognized by serum antibodies. For example, it is well established that BKVs are not generally recognized by antibodies elicited during JCV infection. Although it has long been recognized that different BKV isolates are genetically distinct, no prior work has investigated the possibility that some BKV genotypes are resistant to neutralization by antibodies elicited by other other BKV genotypes. In other words, it is unclear whether distinct serotypes exist within the viral species BKV. This question is also unresolved for JCV. Our lab's work in FY2011 revealed that BKV genotype I (BKV-I) and BKV-IV are distinct serotypes that are reciprocally resistant to antibody-mediated cross-neutralization. Work in FY2012 has revealed that BKV genotypes can be divided into as many as five distinct serotypes. Encouragingly, administration of a multivalent VLP-based vaccine to mice elicits highly potent neutralizing antibody responses capable of neutralizing all five BKV serotypes. This suggests that a multivalent BKV VLP vaccine might be effective for protecting kidney transplant recipients against BKVN. We have recently begun extending our BKV findings to JCV. Specifically, we hypothesize that JCV VP1 variants found in PML lesions may allow the virus to escape from antibody-mediated neutralization. If this hypothesis is true, it would suggest that administering patients a VLP-based vaccine containing PML-variant VP1 might protect patients who are candidates for immunosuppressive therapy against PML. This work is the subject of an NCI patent application submitted in FY12. In FY15 we have began building industry partnerships to develop BKV and JCV vaccines. In FY16 we have developed industry and academic partnerships to investigate BKV- and JCV-neutralizing human monoclonal antibodies. Such antibodies could be of clinical utility for patients and would also provide a practical demonstration that the humoral immunity we seek to stimulate through vaccination will be effective.